Registration Dossier
Registration Dossier
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 204-524-2 | CAS number: 122-14-5
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
A 2 -generation reproductive toxicity study is available for fenitrothion
Link to relevant study records
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 20 April 1989 - 15 September 1989
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- GLP compliance:
- yes
- Limit test:
- no
- Justification for study design:
- Standard study design according to OECD TG416
- Specific details on test material used for the study:
- Fenitrothion
Batch No.: 60553
Purity: 94.6%, - Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crl: CD® (SD)BR
- Details on species / strain selection:
- Standard species/strain used for regulatory studies
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, NC, USA
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 6 weeks
- Weight at study initiation: 199-257 g (M), 151-197 g (F)
- Fasting period before study: no
- Housing: group housed during the premating period, co-habitation during the mating period (1:1), indvidual during gestation and lactation (F)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 16 days - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- Groups of 30 male and 30 female Crl: CD® (SD)BR rats each received fenitrothion in basal diet at concentrations of 0, 10, 40 and 120 ppm for 82-day (P1) or minimum of 88-day (F1a) pre-mating period, up to 21 days mating period, gestation and 28-day (F1a and F2) or 21-day (F1b) lactation period.
- Details on mating procedure:
- Rats were cohoused (1:1) for a maximum of 21 days; the day of mating (evidence of sperm in vaginal smear or presence of copulatory plug) was designated GD0.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Achieved concentrations, stability and homogeneity of the test material in the diet were analysed.
- Duration of treatment / exposure:
- Groups of rats were administered fenitrothion in the diet for 82-day (P1) or minimum of 88-day (F1a) pre-mating period, up to 21 days mating period, gestation and 28-day (F1a and F2) or 21-day (F1b) lactation period.
- Frequency of treatment:
- Daily / continuous in the diet
- Details on study schedule:
- The day on which evidence of mating was observed was designated as Day 0 of gestation. The day on which parturition was completed was designated as Day 1 of lactation. On Day 4 of lactation, the number of F1 pups was reduced to a maximum number of 8 per litter (4 males and 4 females, when possible). Offspring from the first mating (F1a) were maintained through weaning, then 30 animals/sex/group were selected as parental animals for the second generation.
- Dose / conc.:
- 0 ppm
- Remarks:
- Control (basal diet)
- Dose / conc.:
- 10 ppm
- Dose / conc.:
- 40 ppm
- Dose / conc.:
- 120 ppm
- No. of animals per sex per dose:
- 30
- Control animals:
- yes, plain diet
- Details on study design:
- Animals were assigned randomly to dose groups on the basis of bodyweight
- Positive control:
- Not required
- Parental animals: Observations and examinations:
- Body weights and food consumption values for the parental animals were recorded throughout the study.
- Litter observations:
- Litter size and individual pup body weights were recorded during the lactation period.
- Postmortem examinations (parental animals):
- Complete gross necropsies were performed on all parental rats. All gross lesions and vagina, uterus/cervix, ovaries, mammary gland, pituitary gland, testis, epididymides, seminal vesicles, prostate, coagulating gland, pituitary gland and liver of each rat were examined for histopathology.
- Postmortem examinations (offspring):
- The F1a pups not selected as the second generation, F1b and F2 pups were sacrificed with carbon dioxide and examined for gross lesions at weaning.
- Statistics:
- Differences in parameters between the control and test groups were assessed using appropriate statistical techniques.
- Reproductive indices:
- Mating, fertility amd gestation indices were measured for both generations
- Offspring viability indices:
- Viability and lactation indices were measured for both generations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No clinical signs occurred for the male or female rats in the P1 generation as the result of exposure to diets containing the test substance.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Dosage-dependent, statistically significant effects on body weight gains, body weights and absolute and relative feed consumption values occurred for male and female rats given the test substance in the diet at a concentration of 120 ppm. Body weights and body weight gains were significantly affected by the 40 ppm in the F0 generation female rats during lactation.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Dosage-dependent, statistically significant effects on absolute and relative feed consumption values occurred for male and female rats given the test substance in the diet at a concentration of 120 ppm.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment-related microscopic changes were observed in any of the tissues specified for evaluation from male and female F0 rats
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- There were no test substance related effects on reproductive performance
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Key result
- Critical effects observed:
- no
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- During gestation, there tended to be an increase in the number of 120 ppm group F1 female rats with soft or liquid faeces and chromorrhinorrhea. During lactation, there tended to be an increase in the number of 120 ppm group F1 generation female rats with soft or liquid feces and statistically significant increases in the number of 120 ppm group F1 generation female rats with tremors occurred during lactation
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- No deaths and moribund sacrifices occurred as the results of effects of the test substance.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Dosage-dependent, statistically significant effects on body weight gains and body weights occurred for male and female rats given the test substance in the diet at a concentration of 120 ppm. Body weights and body weight gains were significantly affected by the 40 ppm F1 generation male rats during the postcohabitation period.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Dosage-dependent, statistically significant effects on absolute and relative feed consumption values occurred for male and female rats given the test substance in the diet at a concentration of 120 ppm. Absolute feed consumption values were significantly affected by the 40 ppm concentration of the test substance in the F1 generation female rats.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No gross lesions revealed at necropsy were considered as effects of the test substance
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment-related microscopic changes were observed in any of the tissues specified for evaluation from male and female F1 generation rats
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
- Details on results:
- There was no treatment-related mortality or clinical signs. Bodyweights and food consumption were reduced at 40 and 120 ppm. Fertility and reproductive parameters were unaffected by treatment. Gross necropsy did not reveal any treatmnet-related effects.
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- There were no test substance related effects on reproductive performance.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Key result
- Critical effects observed:
- no
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- The number of pups with observations related to morbidity/mortality (e.g. cold to touch, not nursing, weak) was increased at a concentration of 120 ppm
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- The 120 ppm concentration of the test substance was associated with significant increases in mortality.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The 120 ppm concentration of the test substance tended to reduce or significantly reduced pup body weights
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Other effects:
- no effects observed
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1a
- Effect level:
- 40 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1b
- Effect level:
- 40 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- Key result
- Critical effects observed:
- no
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- The number of pups with observations related to morbidity/mortality (e.g. cold to touch, not nursing, weak) was increased in the F2 litters at a concentration of 120 ppm
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- The 120 ppm concentration of the test substance was associated with significant increases in mortality.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The 120 ppm concentration of the test substance tended to reduce or significantly reduced pup body weights.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Gross pathology findings for the offspring were considered incidental in nature and showed no relation to compound administration
- Histopathological findings:
- not examined
- Other effects:
- not examined
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F2
- Effect level:
- 40 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- Key result
- Critical effects observed:
- no
- Key result
- Reproductive effects observed:
- no
- Conclusions:
- No effects on fertililty or reproductive capacity were seen in this study at dose levels sufficient to cause general toxicity in parental rats and offspring. In the absence of any effects, a reproductive NOAEL of 120 ppm (7.4-15.2 mg/kg bw/d) can be determined for this study. A parental NOAEL of 10 ppm (0.7 mg/kg bw/d) can be determined, based on bodyweight effects at higher dose levels. An offspring NOAEL of 40 ppm (2.3-5.4 mg/kg bw/d) can be determined for this study, based on increased mortality and bodyweight effects at the highest dose level.
- Executive summary:
A two-generation reproductive toxicity study was performed in the rat uisng dietary concentrations of fenitrothion of 0, 10, 40 and 120 ppm. Successive generations of rats were exposed for at least 10 weeks prior to mating and throughout mating, gestation and lactation of the tresulting litters. The first generation was mated to produce two litters. Adminstration of the highest dose level resulted in clinical signs, reduced food consumption and bodyweight effects in parental animals. Bodyweight effects were also apparent in parental animals at 40 ppm. There were no effects on fertility in either generation. Increased pup mortality, clinical signs and reduced weight gain were seen in pups of both generations at 120 ppm. No effects on fertililty or reproductive capacity were seen in this study at dose levels sufficient to cause general toxicity in parental rats and offspring. In the absence of any effects, a reproductive NOAEL of 120 ppm (7.4-15.2 mg/kg bw/d) can be determined for this study. A parental NOAEL of 10 ppm (0.7 mg/kg bw/d) can be determined, based on bodyweight effects at higher dose levels. An offspring NOAEL of 40 ppm (2.3-5.4 mg/kg bw/d) can be determined for this study, based on increased mortality and bodyweight effects at the highest dose level.
Reference
Mean intakes (mg/kg bw/d)
Animal |
Dosage group (ppm) |
|||||
10 |
40 |
120 |
||||
Male |
Female |
Male |
Female |
Male |
Female |
|
F0 (Premating) |
0.5 - 1.0 (0.7) |
0.6 - 1.1 (0.7) |
2.2 - 4.3 (2.7) |
2.5 - 4.3 (3.1) |
6.6 - 12.8 (8.0) |
7.8 - 13.5 (9.7)a |
Gestation (F1a) |
|
0.6 |
|
2.7 |
|
7.8 |
Lactation(F1a) |
|
1.3 |
|
5.4 |
|
15.2 |
Gestation (F1b) |
|
0.6 |
|
2.3 |
|
7.4 |
Lactation (F1b) |
|
1.1 |
|
4.5 |
|
12.0 |
F1a (Premating) |
0.7 |
0.8 |
2.8 |
3.3 |
8.8 |
11.1 |
Gestation |
|
0.7 |
|
2.7 |
|
8.6 |
Lactation |
|
1.3 |
|
4.8 |
|
14.1 |
Clinical signs (F1 parental females)
0 ppm |
10 ppm |
40 ppm |
120 ppm |
|
Gestation period |
|
|
|
|
Soft or liquid faeces |
0/ 0 |
7/ 1 |
1/ 1 |
18/ 4 |
Chromorhinorrhoea |
1/ 1 |
2/ 2 |
2/ 2 |
6/ 4 |
Lactation period |
|
|
|
|
Tremors |
0/ 0 |
0/ 0 |
0/ 0 |
43/ 6* |
Soft or liquid faeces |
25/ 4 |
52/ 8 |
73/ 6 |
65/ 10 |
*significantly different to controls (p<0.05)
Summary of pre-mating bodyweights (g) in parental animals
|
Male |
Female |
||||||
0 ppm |
10 ppm |
40 ppm |
120 ppm |
0 ppm |
10 ppm |
40 ppm |
120 ppm |
|
F0 |
|
|
|
|
|
|
|
|
Day 1 |
231.3 |
229.2 |
231.2 |
229.6 |
178.0 |
175.1 |
173.8 |
174.8 |
Day 8 |
299.0 |
219.6 |
295.0 |
288.0** |
209.4 |
206.8 |
208.1 |
201.9 |
Day 15 |
338.0 |
331.1 |
340.0 |
330.0 |
233.7 |
230.1 |
230.2 |
221.2** |
Day 22 |
379.0 |
370.9 |
378.1 |
367.7 |
254.1 |
249.4 |
248.7 |
240.9 |
Day 29 |
414.5 |
405.8 |
415.5 |
400.5 |
273.9 |
267.5 |
267.1 |
256.8** |
Day 36 |
443.7 |
431.2 |
443.5 |
429.9 |
287.2 |
280.7 |
281.8 |
271.1 |
Day 43 |
474.8 |
457.8 |
468.4 |
455.3 |
298.0 |
289.3 |
290.8 |
281.7 |
Day 50 |
506.8 |
486.0* |
499.7 |
482.2* |
308.3 |
299.3 |
300.7 |
291.5 |
Day 57 |
523.6 |
504.7 |
517.3 |
499.4 |
320.0 |
310.4 |
311.5 |
301.6 |
Day 64 |
544.3 |
523.7 |
532.1 |
516.0** |
328.6 |
319.1 |
317.1 |
305.5** |
Day 71 |
561.1 |
538.4* |
552.5 |
533.7* |
332.7 |
322.7 |
325.1 |
311.8 |
Day 78 |
577.3 |
556.2 |
567.5 |
547.2* |
334.5 |
324.6 |
327.2 |
315.7 |
Day 82 |
583.8 |
562.2 |
572.7 |
556.1 |
341.5 |
331.9 |
332.4 |
319.4 |
Termination |
718.3 |
698.2 |
700.9 |
685.9 |
- |
- |
- |
- |
F1 |
|
|
|
|
|
|
|
|
Day 1 |
95.9 |
96.2 |
94.2 |
78.6** |
87.5 |
88.6 |
88.0 |
73.0** |
Day 8 |
160.8 |
157.3 |
156.9 |
125.0** |
136.7 |
135.1 |
135.9 |
109.5** |
Day 15 |
225.4 |
222.8 |
224.5 |
181.5** |
176.1 |
171.8 |
176.8 |
146.9** |
Day 22 |
293.3 |
287.4 |
288.9 |
244.0** |
205.7 |
198.9 |
205.0 |
176.0** |
Day 29 |
350.4 |
348.3 |
346.2 |
299.2** |
229.7 |
222.5 |
231.1 |
198.1** |
Day 36 |
408.5 |
402.6 |
400.9 |
350.9** |
256.8 |
247.7 |
254.2 |
223.1** |
Day 43 |
453.2 |
447.4 |
444.4 |
393.7** |
275.2 |
264.5 |
275.1 |
240.3** |
Day 50 |
489.2 |
483.5 |
476.9 |
427.9** |
290.5 |
277.4 |
289.0 |
255.0** |
Day 57 |
520.4 |
513.8 |
505.7 |
454.7** |
302.4 |
289.0 |
299.5 |
266.2** |
Day 64 |
548.2 |
538.3 |
529.3 |
477.9** |
312.8 |
298.6 |
309.4 |
275.2** |
Day 71 |
574.4 |
563.4 |
553.8 |
500.0** |
322.3 |
305.3* |
318.2 |
281.9** |
Day 78 |
600.2 |
584.7 |
577.0 |
518.1** |
329.6 |
313.7 |
324.5 |
288.7** |
Day 85 |
620.1 |
602.8 |
593.1 |
533.6** |
337.6 |
321.1 |
331.4 |
295.3** |
Termination |
800.6 |
762.9 |
744.5* |
666.1** |
- |
- |
- |
- |
*significantly different to controls (p<0.05); **p<0.01
Summary of female bodyweights during gestation and lactation
Dose level |
0 ppm |
10 ppm |
40 ppm |
120 ppm |
F0 - First gestation |
||||
Day 0 |
338.9 |
329.8 |
322.8 |
314.6 |
Day 6 |
366.2 |
352.6 |
353.3 |
334.6 |
Day 12 |
397.6 |
386.2 |
381.8 |
364.1** |
Day 15 |
399.0 |
393.4 |
389.6 |
372.9 |
Day 20 |
464.3 |
453.9 |
448.0 |
417.6** |
F0 - Second gestation |
||||
Day 0 |
377.6 |
367.7 |
372.9 |
347.0 |
Day 6 |
401.2 |
392.3 |
397.4 |
374.2 |
Day 12 |
426.7 |
418.8 |
421.6 |
400.4 |
Day 15 |
443.6 |
433.9 |
431.9 |
412.5 |
Day 20 |
508.3 |
502.2 |
493.2 |
469.6 |
F1 - gestation |
||||
Day 0 |
346.6 |
339.5 |
338.1 |
306.1** |
Day 6 |
370.1 |
363.9 |
359.8 |
322.4** |
Day 12 |
393.1 |
389.1 |
385.1 |
347.4** |
Day 15 |
407.6 |
403.0 |
401.0 |
361.0** |
Day 20 |
475.0 |
472.5 |
466.3 |
416.9** |
Dose level |
0 ppm |
10 ppm |
40 ppm |
120 ppm |
F0 – first lactation |
||||
Day 1 |
365.7 |
362.6 |
357.0 |
343.4 |
Day 4 |
365.7 |
357.3 |
355.5 |
329.9 |
Day 7 |
366.6 |
363.2 |
356.9 |
326.9** |
Day 10 |
384.3 |
377.0 |
368.7 |
334.2** |
Day 14 |
378.9 |
370.4 |
367.3 |
342.8** |
Day 16 |
388.3 |
380.0 |
368.4* |
346.4** |
Day 18 |
378.1 |
366.3 |
361.4 |
340.4** |
Day 21 |
368.2 |
351.9 |
349.5* |
329.1** |
Day 28 |
351.8 |
344.8 |
338.5 |
325.3 |
F0 – second lactation |
||||
Day 1 |
408.6 |
402.5 |
406.0 |
386.1 |
Day 4 |
409.0 |
403.6 |
398.2 |
378.0 |
Day 7 |
402.8 |
389.4 |
392.6 |
369.5 |
Day 10 |
410.6 |
400.6 |
405.1 |
371.7 |
Day 14 |
410.8 |
400.0 |
399.1 |
368.4** |
Day 16 |
411.6 |
411.3 |
402.6 |
373.7 |
Day 18 |
406.7 |
405.3 |
389.8 |
368.1** |
Day 21 |
391.4 |
385.8 |
379.6 |
367.0 |
F1 – lactation |
||||
Day 1 |
387.5 |
372.7 |
374.4 |
333.0** |
Day 4 |
390.2 |
367.0 |
370.6 |
320.4** |
Day 7 |
388.0 |
369.3 |
372.0 |
319.1** |
Day 10 |
398.9 |
376.9 |
375.4* |
325.9** |
Day 14 |
402.3 |
382.0 |
376.1* |
329.2** |
Day 16 |
405.7 |
389.6 |
383.7 |
339.0** |
Day 18 |
396.9 |
386.2 |
380.0 |
339.2** |
Day 21 |
394.4 |
373.5* |
370.7* |
340.1** |
Day 28 |
370.0 |
348.9* |
358.7 |
328.8** |
*significantly different to controls (p<0.05); **p<0.01
Summary of pre-mating food consumption
|
Male |
Female |
||||||
0 ppm |
10 ppm |
40 ppm |
120 ppm |
0 ppm |
10 ppm |
40 ppm |
120 ppm |
|
F0 |
||||||||
Day 1-8 |
27.0 |
26.2 |
28.4 |
27.6 |
22.4 |
20.4** |
20.5** |
20.5** |
Day 8-15 |
29.3 |
29.8 |
29.8 |
29.1 |
24.0 |
22.9 |
23.0 |
23.7 |
Day 15-22 |
26.6 |
26.0 |
26.9 |
25.7 |
21.3 |
20.2 |
21.3 |
22.2 |
Day 22-29 |
27.6 |
27.1 |
27.4 |
26.5 |
22.0 |
20.8 |
21.1 |
20.8 |
Day 29-36 |
28.2 |
26.5 |
27.8 |
27.2 |
22.0 |
21.3 |
21.5 |
21.6 |
Day 36-43 |
28.0 |
27.2 |
27.6 |
27.2 |
21.8 |
20.2 |
20.6 |
21.1 |
Day 43-50 |
28.0 |
26.7 |
27.6 |
26.7 |
21.4 |
19.9 |
20.3 |
20.6 |
Day 50-57 |
28.0 |
27.4 |
27.8 |
27.2 |
21.0 |
19.5 |
20.0 |
19.7 |
Day 57-64 |
28.6 |
27.8 |
28.7 |
28.2 |
21.1 |
20.0 |
20.7 |
20.4 |
Day 64-71 |
28.8 |
28.4 |
29.1 |
27.7 |
21.8 |
20.3 |
21.0 |
20.0 |
Day 71-78 |
29.6 |
28.8 |
29.4 |
28.6 |
22.1 |
20.7 |
21.3 |
20.7 |
Day 78-82 |
31.5 |
31.0 |
31.3 |
30.2 |
22.2 |
20.3 |
20.8 |
20.6* |
F1 |
||||||||
Day 1-8 |
17.7 |
17.2 |
17.6 |
15.1** |
15.5 |
15.0 |
15.7 |
13.9* |
Day 8-15 |
24.6 |
24.2 |
25.1 |
21.5** |
19.8 |
19.0 |
20.1 |
18.6 |
Day 15-22 |
28.0 |
27.8 |
28.3 |
25.4* |
20.8 |
19.5* |
20.6 |
20.8 |
Day 22-29 |
30.4 |
30.3 |
31.1 |
28.1* |
21.8 |
20.5 |
22.1 |
22.1 |
Day 29-36 |
32.4 |
31.6 |
32.4 |
29.9** |
23.0 |
22.0 |
22.1 |
22.0 |
Day 36-43 |
32.4 |
32.3 |
32.6 |
29.8** |
23.2 |
21.7 |
23.1 |
22.4 |
Day 43-50 |
32.4 |
32.4 |
32.3 |
29.7** |
23.2 |
22.0 |
22.7 |
22.6 |
Day 50-57 |
32.1 |
32.0 |
32.0 |
29.3** |
23.4 |
21.4* |
21.8* |
22.1 |
Day 57-64 |
32.6 |
32.2 |
32.1 |
29.0** |
23.3 |
21.6 |
22.2 |
21.5 |
Day 64-71 |
32.3 |
31.8 |
31.3 |
28.7** |
23.2 |
20.9** |
21.5* |
20.8* |
Day 71-78 |
33.0 |
32.2 |
32.0 |
28.6** |
22.8 |
21.4 |
21.1** |
21.1 |
Day 78-85 |
34.2 |
33.1 |
33.8 |
30.1** |
24.1 |
22.9 |
22.8 |
22.8 |
*significantly different to controls (p<0.05); **p<0.01
Summary of food consumption in females during gestation and lactation
Dose level |
0 ppm |
10 ppm |
40 ppm |
120 ppm |
F0 – first gestation |
||||
Day 0-6 |
26.3 |
23.5* |
25.6 |
22.7** |
Day 6-12 |
27.9 |
26.7 |
26.9 |
26.0 |
Day 12-15 |
23.7 |
22.3 |
24.9 |
25.2 |
Day 15-20 |
26.7 |
26.1 |
25.8 |
23.1 |
F0 - second gestation |
||||
Day 0-6 |
24.5 |
24.1 |
23.2 |
24.0 |
Day 6-12 |
26.1 |
25.4 |
24.8 |
25.4 |
Day 12-15 |
26.9 |
25.9 |
24.6 |
25.8 |
Day 15-20 |
24.4 |
24.2 |
24.6 |
24.7 |
F1 - gestation |
||||
Day 0-6 |
25.8 |
25.6 |
24.4 |
22.7 |
Day 6-12 |
27.3 |
27.2 |
26.5 |
26.0 |
Day 12-15 |
28.6 |
29.2 |
28.4 |
26.5 |
Day 15-20 |
27.8 |
28.8 |
28.3 |
25.7 |
F0 f -first lactation |
||||
Day 1-4 |
34.3 |
38.0 |
35.3 |
32.0 |
Day 4-7 |
43.6 |
40.7 |
44.7 |
43.0 |
Day 7-10 |
54.8 |
53.8 |
54.6 |
41.9** |
Day 10-14 |
62.4 |
61.0 |
60.1 |
53.6 |
F0 - second lactation |
||||
Day 1-4 |
30.0 |
28.2 |
31.3 |
24.7 |
Day 4-7 |
37.0 |
37.8 |
39.9 |
30.9** |
Day 7-10 |
49.1 |
50.1 |
49.2 |
41.8** |
Day 10-14 |
54.8 |
55.4 |
55.0 |
47.8 |
F1 - lactation |
||||
Day 1-4 |
30.2 |
28.9 |
28.1 |
23.6 |
Day 4-7 |
44.5 |
41.7 |
39.0 |
31.0** |
Day 7-10 |
55.2 |
50.9 |
48.3** |
39.6** |
Day 10-14 |
65.4 |
61.7 |
56.8** |
51.9** |
*significantly different to controls (p<0.05); **p<0.01
Summary of reproductive parameters (F1a litters)
Dose level |
0 ppm |
10 ppm |
40 ppm |
120 ppm |
Parental reproduction indices |
||||
Total No. of males placed with females |
30 |
30 |
30 |
30 |
Total No. of males mated with females |
27 |
27 |
26 |
25 |
Total No. of mated males resulting in pregnancy |
25 |
19 |
17 |
19 |
Male mating index (%) |
90.0 |
90.0 |
86.7 |
83.3 |
Male fertility index (%) |
83.3 |
63.3 |
56.7 |
63.3 |
Total No. of females placed with males |
30 |
30 |
30 |
30 |
Total No. of females showing evidence of mating |
28 |
29 |
29 |
29 |
Total No. of females pregnant |
26 |
20 |
19 |
21 |
Female mating index (%) |
93.3 |
96.7 |
96.7 |
96.7 |
Pregnancy rate (%) |
92.8 |
69.0 |
65.5 |
72.4 |
No. of females delivering offspring |
26 |
19a |
19 |
21 |
No. of females delivering viable offspring |
26 |
19 |
19 |
21 |
Parturition index (%) |
100 |
100 |
100 |
100 |
Offspring indices |
||||
Mean No. of live pups at parturition/litter |
14.6 |
14.6 |
12.8 |
12.2 |
Mean No. of stillborn/litter |
0.2 |
0.0 |
0.2 |
0.3 |
Viability index (%) |
96.8 |
99.3 |
98.4 |
86.0** |
Lactation index (%) |
99.0 |
100.0 |
100.0 |
91.5** |
Number of surviving pups/litter |
||||
Day 1 |
14.6 |
14.6 |
12.8 |
12.2 |
Day 4 (pre-cull) |
14.1 |
14.5 |
12.6 |
10.5* |
Day 4 (post-cull) |
8.0 |
7.7 |
7.7 |
6.7* |
Day 7 |
8.0 |
7.7 |
7.7 |
6.3* |
Day 14 |
7.9 |
7.7 |
7.7 |
6.2* |
Day 21 |
7.9 |
7.7 |
7.7 |
6.2* |
Day 28 |
7.9 |
7.7 |
7.7 |
6.1** |
Mean pup weight/litter (g) |
||||
Day 1 |
6.5 |
6.5 |
6.8 |
6.2 |
Day 4 (pre-cull) |
9.8 |
9.5 |
10.0 |
8.8 |
Day 4 (post-cull) |
9.8 |
9.5 |
10.2 |
8.9 |
Day 7 |
16.5 |
15.8 |
16.8 |
13.8 |
Day 14 |
35.2 |
34.9 |
35.4 |
28.7** |
Day 21 |
55.0 |
54.3 |
54.1 |
45.9** |
Percent male pups (%) |
||||
Day 1 |
45.5 |
51.0 |
49.2 |
53.9 |
Day 4 (pre-cull) |
45.0 |
51.4 |
48.8 |
53.0 |
Day 4 (post-cull) |
49.0 |
48.0 |
49.6 |
53.2 |
Day 7 |
49.3 |
48.0 |
49.6 |
53.0 |
Day 14 |
49.0 |
48.0 |
49.6 |
53.0 |
Day 21 |
49.0 |
48.0 |
49.6 |
53.0 |
Day 28 |
49.0 |
48.0 |
49.6 |
52.6 |
*significantly different to controls (p<0.05); **p<0.01
Summary of reproductive parameters (F1b litters)
Dose level |
0 ppm |
10 ppm |
40 ppm |
120 ppm |
Parental reproduction indices |
||||
Total No. of males placed with females |
30 |
28a |
30 |
30 |
Total No. of males mated with females |
25 |
23 |
23 |
17* |
Total No. of mated males resulting in pregnancy |
22 |
18 |
17 |
14 |
Male mating index (%) |
83.3 |
82.1 |
76.7 |
56.7* |
Male fertility index (%) |
73.3 |
64.3 |
56.7 |
46.7 |
Total No. of females placed with males |
30 |
28 |
30 |
30 |
Total No. of females showing evidence of mating |
27 |
25 |
25 |
20 |
Total No. of females pregnant |
24 |
19 |
18 |
16 |
Female mating index (%) |
90.0 |
89.3 |
83.3 |
66.7 |
Pregnancy rate (%) |
88.9 |
76.0 |
72.0 |
80.0 |
No. of females delivering offspring |
24 |
19 |
17 |
14b |
No. of females delivering viable offspring |
24 |
19 |
16c |
14 |
Parturition index (%) |
100.0 |
100.0 |
94.1 |
100.0 |
Offspring indices |
||||
Mean No. of live pups at parturition/litter |
14.4 |
15.1 |
12.7 |
12.3 |
Mean No. of stillborn/litter |
0.1 |
0.4 |
0.3 |
0.0 |
Viability index (%) |
96.8 |
98.6 |
98.0 |
97.7 |
Lactation index (%) |
100.0 |
94.7** |
100.0 |
96.3* |
Number of surviving pups/litter |
|
|
|
|
Day 1 |
14.4 |
15.1 |
12.7 |
12.3 |
Day 4 (precull) |
14.0 |
14.9 |
12.4 |
12.0 |
Day 4 (postcull) |
7.7 |
8.0 |
7.5 |
7.6 |
Day 7 |
7.7 |
8.0 |
7.5 |
7.5 |
Day 14 |
7.7 |
8.0 |
7.5 |
7.4 |
Day 21 |
7.7 |
8.0 |
7.5 |
7.4 |
Mean pup weight/litter (g) |
||||
Day 1 |
6.7 |
6.5 |
6.8 |
6.5 |
Day 4 (precull) |
10.2 |
9.6 |
10.8 |
9.7 |
Day 4 (postcull) |
10.3 |
9.6 |
10.9 |
9.8 |
Day 7 |
17.0 |
16.0 |
17.9 |
14.6 |
Day 14 |
36.6 |
34.8 |
37.9 |
29.6** |
Day 21 |
56.2 |
55.3 |
57.9 |
47.6** |
Percent male pups (%) |
||||
Day 1 |
51.1 |
48.1 |
47.3 |
47.1 |
Day 4 (precull) |
52.1 |
48.2 |
46.3 |
47.9 |
Day 4 (postcull) |
51.4 |
48.7 |
48.4 |
48.6 |
Day 7 |
51.4 |
48.7 |
48.4 |
48.6 |
Day 14 |
51.4 |
48.7 |
48.4 |
49.6 |
Day 21 |
51.4 |
48.6 |
48.4 |
49.6 |
*significantly different to controls (p<0.05); **p<0.01
Summary of reproductive parameters (F2 litters)
Dose level |
0 ppm |
10 ppm |
40 ppm |
120 ppm |
Parental reproduction indices |
||||
Total No. of males placed with females |
29a |
30 |
30 |
30 |
Total No. of males mated with females |
24 |
24 |
22 |
21 |
Total No. of mated males resulting in pregnancy |
18 |
21 |
21 |
17 |
Male mating index (%) |
82.8 |
80.0 |
73.3 |
70.0 |
Male fertility index (%) |
62.1 |
70.0 |
70.0 |
56.7 |
Total No. of females placed with males |
29b |
30 |
30 |
30 |
Total No. of females showing evidence of mating |
27 |
27 |
26 |
28 |
Total No. of females pregnant |
19 |
23 |
24 |
21 |
Female mating index (%) |
93.1 |
90.0 |
86.7 |
93.3 |
Pregnancy rate (%) |
70.4 |
85.2 |
92.3 |
75.0 |
No. of females delivering offspring |
18c |
23 |
24 |
20d |
No. of females delivering viable offspring |
18 |
23 |
24 |
20 |
Parturition index (%) |
100 |
100 |
100 |
100 |
Offspring indices |
||||
Mean No. of live pups at parturition/litter |
13.6 |
13.7 |
13.0 |
12.4 |
Mean No. of stillborn/litter |
0.2 |
0.2 |
0.1 |
0.2 |
Viability index (%) |
99.6 |
99.0 |
99.7 |
85.5** |
Lactation index (%) |
100.0 |
100.0 |
99.4 |
89.8** |
Number of surviving pups/litter |
||||
Day 1 |
13.6 |
13.7 |
13.0 |
12.4 |
Day 4 (precull) |
13.6 |
13.6 |
13.0 |
10.6 |
Day 4 (postcull) |
8.0 |
7.9 |
7.4 |
6.8 |
Day 7 |
8.0 |
7.9 |
7.4 |
6.6* |
Day 14 |
8.0 |
7.9 |
7.4 |
6.2* |
Day 21 |
8.0 |
7.9 |
7.4 |
6.2* |
Day 28 |
8.0 |
7.9 |
7.4 |
6.2* |
Mean pup weight/litter (g) |
||||
Day 1 |
6.8 |
6.7 |
6.6 |
6.5 |
Day 4 (precull) |
10.4 |
9.9 |
9.6 |
8.4** |
Day 4 (postcull) |
10.4 |
10.0 |
9.6 |
8.4* |
Day 7 |
17.0 |
16.5 |
15.8 |
12.1** |
Day 14 |
36.4 |
35.0 |
34.0 |
26.8** |
Day 21 |
58.2 |
56.2 |
54.4 |
44.0** |
Percent male pups (%) |
||||
Day 1 |
46.5 |
49.2 |
50.0 |
56.4 |
Day 4 (precull) |
46.7 |
49.3 |
50.0 |
57.2 |
Day 4 (postcull) |
48.6 |
49.6 |
50.3 |
54.9 |
Day 7 |
48.6 |
49.6 |
50.3 |
54.2 |
Day 14 |
48.6 |
49.6 |
50.3 |
57.4 |
Day 21 |
48.6 |
49.6 |
50.6 |
57.4 |
Day 28 |
48.6 |
49.6 |
50.6 |
57.4 |
Summary of litter observations
|
F1a |
F2 |
||||||
0 ppm |
10 ppm |
40 ppm |
120 ppm |
0 ppm |
10 ppm |
40 ppm |
120 ppm |
|
Litters examined (N) |
26 |
19 |
19 |
21 |
18 |
23 |
24 |
20 |
Small and weak |
2/2 |
0/0 |
0/0 |
14/5 |
0/0 |
0/0 |
0/0 |
0/0 |
Thin appearance |
0/0 |
0/0 |
0/0 |
3/1 |
0/0 |
0/0 |
0/0 |
0/0 |
Weak |
0/0 |
0/0 |
0/0 |
22/2 |
0/0 |
0/0 |
0/0 |
21/3 |
Cold to touch |
0/0 |
2/1 |
17/2 |
61/4 |
0/0 |
0/0 |
5/2 |
56/4 |
Pup not nursing |
1/1 |
0/0 |
0/0 |
14/3 |
0/0 |
0/0 |
0/0 |
53/3 |
Pale appearance |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
22/3 |
White substance surrounding umbilicus |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
1/1 |
Tremors |
0/0 |
0/0 |
0/0 |
2/1 |
0/0 |
0/0 |
1/1 |
0/0 |
Urine-stained abdominal fur |
0/0 |
0/0 |
0/0 |
1/1 |
0/0 |
0/0 |
0/0 |
0/0 |
Lesion |
0/0 |
0/0 |
0/0 |
4/2c |
0/0 |
0/0 |
0/0 |
11/1 |
Bite wound |
0/0 |
0/0 |
0/0 |
2/1 |
0/0 |
0/0 |
2/1b |
11/1 |
Right front leg and paw missing |
0/0 |
0/0 |
0/0 |
3/1 |
0/0 |
0/0 |
0/0 |
0/0 |
Tail missing |
0/0 |
0/0 |
29/2 |
3/1 |
0/0 |
0/0 |
4/1 |
25/1 |
Back discolored |
0/0 |
0/0 |
0/0 |
2/1 |
0/0 |
0/0 |
0/0 |
0/0 |
Mouth discolored |
2/1 |
0/0 |
0/0 |
2/1 |
0/0 |
0/0 |
0/0 |
0/0 |
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 8 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- A guideline-compliant 2-generation reproductive toxicity study is available for fenitrothion
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
A two-generation reproductive toxicity study was performed in the rat uisng dietary concentrations of fenitrothion of 0, 10, 40 and 120 ppm. Successive generations of rats were exposed for at least 10 weeks prior to mating and throughout mating, gestation and lactation of the tresulting litters. The first generation was mated to produce two litters. Adminstration of the highest dose level resulted in clinical signs, reduced food consumption and bodyweight effects in parental animals. Bodyweight effects were also apparent in parental animals at 40 ppm. There were no effects on fertility in either generation. Increased pup mortality, clinical signs and reduced weight gain were seen in pups of both generations at 120 ppm. No effects on fertililty or reproductive capacity were seen in this study at dose levels sufficient to cause general toxicity in parental rats and offspring. In the absence of any effects, a reproductive NOAEL of 120 ppm (7.4-15.2 mg/kg bw/d) can be determined for this study. A parental NOAEL of 10 ppm (0.7 mg/kg bw/d) can be determined, based on bodyweight effects at higher dose levels. An offspring NOAEL of 40 ppm (2.3-5.4 mg/kg bw/d) can be determined for this study, based on increased mortality and bodyweight effects at the highest dose level.
Effects on developmental toxicity
Description of key information
Studies of developmental toxicity in the rat and rabbit are available for fenitrothion.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 16 December 1985 - 17 January 1986
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- Fenitrothion
Batch No.: 41208
Purity: 96.6% - Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Hazelton, Denver
- Age at study initiation: 4 months
- Weight at study initiation: 2.7-3.2 kg
- Housing: Individual
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 28 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-23
- Humidity (%): 15-64
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 16 December 1985 To: 17 January 1986 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- Groups of 16 inseminated female HRA(NZW)SPF rabbits each received fenitrothion dissolved in corn oil, at dose levels of 0, 3, 10 and 30 mg/kg bw/d by oral gavage, daily from Days 7 to 19 of gestation at a dosage volume of 1.0 mL/kg bw.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Reserve samples of the dosing solutions were analysed for stability and achieved concentration.
- Details on mating procedure:
- Ovulation was induced in each females by iv injection of 250 IU HCG; females were inseminated with the sperm of males from the same strain on two occasions. The day of inseminatiom was designated GD0.
- Duration of treatment / exposure:
- GD7-19 (13 consecutive days).
- Frequency of treatment:
- Daily
- Duration of test:
- Dams were terminated on GD 29
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- Vehicle control
- Dose / conc.:
- 3 mg/kg bw/day
- Dose / conc.:
- 10 mg/kg bw/day
- Dose / conc.:
- 30 mg/kg bw/day
- No. of animals per sex per dose:
- 16 inseminated females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Doses were selcetd on the basis of range-finding studies in pregnant and non-pregnant rabbits. Animals were assigned to the treatment groups using a weight randomisation technique.
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: GD 0, 7, 8, 9, 13, 16, 19, 20, 23, 26, 29
FOOD CONSUMPTION: Yes
- Time schedule for examinations: GD 0, 7, 8, 9, 13, 16, 19, 20, 23, 26, 29
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29 - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter - Statistics:
- Data were analysed and test groups compared to the controls using appropriate statistical techniques
- Indices:
- Not applicable
- Historical control data:
- Not required for this study
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Anorexia was frequently noted in all groups during the treatment and posttreatment periods. Treatment-related clinical signs in rabbits receiving 30 mg/kg bw/d included reduction in motor activity, salivation, dyspnoea, and tremors. These signs were not seen in any animals of the control, 3 and 10 mg/kg bw/d groups at the pre-treatment and post-treatment intervals, with only one incidence of reduced motor activity (10 mg/kg bw/d group) noted during treatment, in the decedent rabbit.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- A total of six pregnant females receiving 30 mg/kg/ bwd were found dead during the treatment period and three pregnant females aborted or delivered prematurely (GD 22-29). One female receiving 10 mg/kg bw/d was found dead on GD18, and one control female was found dead on GD 8. Both females were anorexic prior to death. The two deaths in the 3 mg/kg bw/d group were the result of dosing errors (verified at necropsy).
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean body weight changes were significantly decreased for pregnant females receiving 30 mg/kg bw/d on GD7-13. These animals also displayed values slightly lower than the control for GD0-29 but this difference was not statistically significant.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Significantly decreased food consumption values were observed for pregnant females receiving 3 mg/kg bw/d on GD9-13 and were significantly increased for animals receiving 30 mg/kg bw/d on GD26-29 in addition to a significant negative trend on GD7-8. All other mean food consumption values were statistically similar for all groups.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- The findings were considered to be incidental and not related to treatment.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Number of abortions:
- effects observed, treatment-related
- Description (incidence and severity):
- Three pregnant females at 30 mg/kg bw/d aborted or delivered prematurely (GD 22-29).
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- effects observed, treatment-related
- Other effects:
- no effects observed
- Details on maternal toxic effects:
- A total of six pregnant females receiving 30 mg/kg/ bwd were found dead during the treatment period and three pregnant females aborted or delivered prematurely (GD 22-29). One female receiving 10 mg/kg bw/d was found dead on GD18, and one control female was found dead on GD 8. Both females were anorexic prior to death. The two deaths in the 3 mg/kg bw/d group were the result of dosing errors (verified at necropsy). Anorexia was frequently noted in all groups during the treatment and posttreatment periods. Treatment-related clinical signs in rabbits receiving 30 mg/kg bw/d included reduction in motor activity, salivation, dyspnoea, and tremors. These signs were not seen in any animals of the control, 3 and 10 mg/kg bw/d groups at the pre-treatment and Mean body weight changes were significantly decreased for pregnant females receiving 30 mg/kg bw/d on GD7-13. These animals also displayed values slightly lower than the control for GD0-29 but this difference was not statistically significant.post-treatment intervals, with only one incidence of reduced motor activity (10 mg/kg bw/d group) noted during treatment, in the decedent rabbit. Significantly decreased food consumption values were observed for pregnant females receiving 3 mg/kg bw/d on GD9-13 and were significantly increased for animals receiving 30 mg/kg bw/d on GD26-29 in addition to a significant negative trend on GD7-8. All other mean food consumption values were statistically similar for all groups. Gross necropsy diod not reveal any effects of treatment.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- mortality
- Key result
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- effects observed, treatment-related
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Other effects:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- The mean number of implantations was lower in the high dose group, resulting in a lower litter size. Other parameters were unaffected by treatment. There was no dose-related increase in the incidence of any particular malformation or in the incidence of any type (i.e. external, visceral, or skeletal) of malformation. Although the litter incidence of skeletal malformations was slightly higher than controls in the 3 and 10 mg/kg bw/d groups, no malformations were noted in the seven litters of the 30 mg/kg bw/d group available for evaluation. Overt evidence of maternal toxicity was seen in animals receiving 30 mg/kg/ bwd but was not accompanied by adverse effects on fetal growth or development
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- Key result
- Abnormalities:
- no effects observed
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 30 mg/kg bw/day
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects as a secondary non-specific consequence of maternal toxicity effects
- Dose response relationship:
- yes
- Relevant for humans:
- no
- Conclusions:
- Maternal and developmental NOAELs of 10 mg/kg bw/d can be determined for this study, based on maternal toxicity (mortality, clinical signs, bodyweight effects) and reduced litter size at the highest dose level.
- Executive summary:
In a developmental toxicity study, groups of 16 inseminated female HRA(NZW)SPF rabbits each received fenitrothion dissolved in corn oil, at dose levels of 0, 3, 10 and 30 mg/kg bw/d by oral gavage, daily from Days 7 to 19 of gestation at the dosage volume of 1.0 mL/kg bw. Clinical observations, body weights and food consumption were recorded for all females. On day 29 of gestation, all surviving pregnant females were sacrificed and a cesarean section performed. All live fetuses were evaluated for external findings, visceral findings (Staples' technique) and for skeletal findings following staining with Alizarin Red S. A total of six pregnant females receiving 30 mg/kg/ bwd were found dead during the treatment period and three pregnant females aborted or delivered prematurely (GD 22-29). One female receiving 10 mg/kg bw/d was found dead on GD18, and one control female was found dead on GD 8. Both females were anorexic prior to death. The two deaths in the 3 mg/kg bw/d group were the result of dosing errors (verified at necropsy). Anorexia was frequently noted in all groups during the treatment and posttreatment periods. Treatment-related clinical signs in rabbits receiving 30 mg/kg bw/d included reduction in motor activity, salivation, dyspnoea, and tremors. These signs were not seen in any animals of the control, 3 and 10 mg/kg bw/d groups at the pre-treatment and Mean body weight changes were significantly decreased for pregnant females receiving 30 mg/kg bw/d on GD7-13. These animals also displayed values slightly lower than the control for GD0-29 but this difference was not statistically significant.post-treatment intervals, with only one incidence of reduced motor activity (10 mg/kg bw/d group) noted during treatment, in the decedent rabbit. Significantly decreased food consumption values were observed for pregnant females receiving 3 mg/kg bw/d on GD9-13 and were significantly increased for animals receiving 30 mg/kg bw/d on GD26-29 in addition to a significant negative trend on GD7-8. All other mean food consumption values were statistically similar for all groups. Gross necropsy did not reveal any effects of treatment. The mean number of implantations was lower in the high dose group, resulting in a lower litter size. Other parameters were unaffected by treatment. There was no dose-related increase in the incidence of any particular malformation or in the incidence of any type (i.e. external, visceral, or skeletal) of malformation. Although the litter incidence of skeletal malformations was slightly higher than controls in the 3 and 10 mg/kg bw/d groups, no malformations were noted in the seven litters of the 30 mg/kg bw/d group available for evaluation. Overt evidence of maternal toxicity was seen in animals receiving 30 mg/kg/ bwd but was not accompanied by adverse effects on foetal growth or development. Maternal and developmental NOAELs of 10 mg/kg bw/d can be determined for this study, based on maternal toxicity (mortality, clinical signs, bodyweight effects) and reduced litter size at the highest dose level.
The highest dose level in this study was sufficient to cause maternal toxicity (including mortality) and was associated with a slight reduction in implantations and litter size. Findings are considered to be secondary to maternal effects.
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 8 April 1986 - 2 May 1986
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- Fenitrothion
Batch No.: 41208
Purity: 96.6% - Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crl:CD®(SD)BR
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, NY
- Age at study initiation: 10-12 weeks
- Weight at study initiation: 199.8-259.1 g
- Housing: Individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 13 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-26
- Humidity (%): 30-70
- Air changes (per hr): 18.2
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 8 April 1986 To: 2 May 1986 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- Groups of 24 time-mated female Sprague-Dawley Crl:CD®(SD)BR rats were gavaged with fenitrothion (dissolved in corn oil) at dose levels of 0, 3, 8 and 25 mg/kg bw/d from Gestation Days 6-15 of gestation, using a dose volume of 5 mL/kg bw.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Achieved concentration and stability were assessed
- Details on mating procedure:
- Rats were mated (1:1) with males of the same strain and source until mating was confirmed and for a maximum of 4 days. The day of mating (as indicated by copulatory plug or vaginal sperm) was designated Gestation Day (GD) 0.
- Duration of treatment / exposure:
- 10 days (GD 6-15)
- Frequency of treatment:
- Daily
- Duration of test:
- Dams were terminated on GD20
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- Vehicle (corn oil) control
- Dose / conc.:
- 3 mg/kg bw/day
- Dose / conc.:
- 8 mg/kg bw/day
- Dose / conc.:
- 25 mg/kg bw/day
- No. of animals per sex per dose:
- 24 time-mated females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Mated females were randomly assigned to the dose groups
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: GD0, 6-19, 20
FOOD CONSUMPTION: Yes
- Time schedule for examinations: GD6-19, 20
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on GD20 - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter - Statistics:
- Differences between the control and treated groups were assessed using appropriate statistical tests.
- Indices:
- Not applicable
- Historical control data:
- Not required
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Signs of toxicity noted at 25 mg/kg bw/d during the treatment and post-treatment intervals included tremors, rough hair, thin appearance, rhinorrhoea and urine staining.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- All females survived until the scheduled sacrifice.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- There was a significant decrease in the mean maternal body weights each day on GD11-19 at 25 mg/kg bw/d. The mean terminal (GD20) bodyweight in the 25 mg/kg bw/d group was slightly, but not significantly, less than the control value. However, the mean corrected terminal body weight was significantly less in the 25 mg/kg bw/d group when compared to controls. The mean maternal body weight gain values were significantly lower in the 25 mg/kg bw/d group during the treatment period compared to the control group. The mean body weight gain values in the 3 and 8 mg/kg/ bw/d groups were significantly above the control values for the post-treatment period.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption values were comparable between the control and treated groups.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- Mean gravid uterine weights were significantly higher for the 3 and 8 mg/kg bw/d groups when compared to the control value. Mean gravid uterine weight at 25 mg/kg bw/d was similar to the controls.
- Details on results:
- All females survived until the scheduled sacrifice. Signs of toxicity noted at 25 mg/kg bw/d during the treatment and post-treatment intervals included tremors, rough hair, thin appearance, rhinorrhoea and urine staining. There was a significant decrease in the mean maternal body weights each day on GD11-19 at 25 mg/kg bw/d. The mean terminal (GD20) bodyweight in the 25 mg/kg bw/d group was slightly, but not significantly, less than the control value. However, the mean corrected terminal body weight was significantly less in the 25 mg/kg bw/d group when compared to controls. The mean maternal body weight gain values were significantly lower in the 25 mg/kg bw/d group during the treatment period compared to the control group. The mean body weight gain values in the 3 and 8 mg/kg/day groups were significantly above the control values for the post-treatment period. Food consumption values were comparable between the control and treated groups. Gross necropsy did not reveal any effects of treatment. Mean gravid uterine weights were significantly higher for the 3 and 8 mg/kg bw/d groups when compared to the control value. Mean gravid uterine weight at 25 mg/kg bw/d was similar to the controls.
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- not examined
- Other effects:
- no effects observed
- Details on maternal toxic effects:
- Parameters were comparable in all groups and were unaffected by treatment.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 8 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- Key result
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Other effects:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- There were no differences between groups in the pregnancy rates, mean implantation efficiency, foetal viability, foetal sex ratio, or mean foetal body weights. Neither the frequency nor the distribution of foetal malformations indicated a teratogenic response in any group in this study.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 25 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Abnormalities:
- no effects observed
- Key result
- Developmental effects observed:
- no
- Conclusions:
- A maternal NOAEL of 8 mg/kg bw/d can be determined for this study, based on clinical signs and bodyweight effects at the highest dose level of 25 mg/kg bw/d. A developmental NOAEL of 25 mg/kg bw/d can be determined in the absence of any effects at the highest dose level.
- Executive summary:
In a developmental toxicity study, groups of 24 time-mated female Sprague-Dawley Crl:CD®(SD)BR rats were gavaged with fenitrothion (dissolved in corn oil) at dose levels of 0, 3, 8 and 25 mg/kg bw/d from Gestation Days 6-15 of gestation, using a dose volume of 5 mL/kg bw. Dams were sacrificed on GD20 and the uterine contents examined. All foetuses were assessed for extranal findings. Approximately one half of the foetuses in each litter were preserved in Bouin's and assessed for visceral findings using Wilson's technique; the remaining foetuses were assessed for skeletal findings following staining with Alizarin Red S. All females survived until the scheduled sacrifice. Signs of toxicity noted at 25 mg/kg bw/d during the treatment and post-treatment intervals included tremors, rough hair, thin appearance, rhinorrhoea and urine staining. There was a significant decrease in the mean maternal body weights each day on GD11-19 at 25 mg/kg bw/d. The mean terminal (GD20) bodyweight in the 25 mg/kg bw/d group was slightly, but not significantly, less than the control value. However, the mean corrected terminal body weight was significantly less in the 25 mg/kg bw/d group when compared to controls. The mean maternal body weight gain values were significantly lower in the 25 mg/kg bw/d group during the treatment period compared to the control group. The mean body weight gain values in the 3 and 8 mg/kg bw/d groups were significantly above the control values for the post-treatment period. Food consumption values were comparable between the control and treated groups. Gross necropsy did not reveal any effects of treatment. Mean gravid uterine weights were significantly higher for the 3 and 8 mg/kg bw/d groups when compared to the control value. Mean gravid uterine weight at 25 mg/kg bw/d was similar to the controls. There were no differences between groups in the pregnancy rates, mean implantation efficiency, foetal viability, foetal sex ratio, or mean foetal body weights. Neither the frequency nor the distribution of foetal malformations indicated a teratogenic response in any group in this study. There was no evidence of teratogenicity or developmental toxicity in this study at dose levels sufficient to result in mild maternal toxicity. A maternal NOAEL of 8 mg/kg bw/d can be determined for this study, based on clinical signs and bodyweight effects at the highest dose level of 25 mg/kg bw/d. A developmental NOAEL of 25 mg/kg bw/d can be determined in the absence of any effects at the highest dose level.
Referenceopen allclose all
Summary of maternal findings
Dose level |
0 mg/kg bw/d |
3 mg/kg bw/d |
10 mg/kg bw/d |
30 mg/kg bw/d |
GD 7-19 (treatment period) |
||||
Number of animals observed |
16 |
16 |
16 |
16 |
Found dead |
1 |
0 |
1 |
6 |
Accidental death |
0 |
2 |
0 |
0 |
Reduction in motor activity |
0 |
0 |
1 |
14 |
Salivation |
0 |
0 |
0 |
14 |
Dyspnoea |
0 |
0 |
0 |
14 |
Tremors |
0 |
0 |
0 |
14 |
GD 20-29 (post-treatment period) |
||||
Number of animals observed |
15 |
14 |
15 |
10 |
Premature delivery/abortion |
0 |
0 |
0 |
3 |
Reduction in motor activity |
0 |
0 |
0 |
1 |
Food consumption (g) |
||||
GD 0-7 |
1124 |
1137 |
1161 |
1183 |
GD 7-8 |
126 |
102 |
108 |
91 |
GD 8-9 |
138 |
112 |
134 |
104 |
GD 9-13 |
548 |
441* |
531 |
465 |
GD 13-16 |
329 |
316 |
307 |
296 |
GD 16-19 |
364 |
221 |
307 |
294 |
GD 19-20 |
95 |
101 |
107 |
83 |
GD 20-23 |
385 |
372 |
372 |
403 |
GD 23-26 |
333 |
352 |
314 |
387 |
GD 26-29 |
278 |
396 |
307 |
457* |
Bodyweight change (g) |
||||
GD 0-7 |
169 |
149 |
166 |
148 |
GD 7-8 |
-31 |
-42 |
-47 |
-48 |
GD 7-9 |
-10 |
-38 |
-18 |
-68 |
GD 7-13 |
51 |
-2 |
29 |
-62* |
GD 7-16 |
45 |
33 |
61 |
-83 |
GD 7-19 |
92 |
-25 |
27 |
-73 |
GD 7-20 |
85 |
-9 |
35 |
-104 |
GD 7-23 |
168 |
63 |
87 |
4 |
GD 7-26 |
192 |
114 |
141 |
50 |
GD 7-29 |
228 |
203 |
192 |
141 |
*significantly different to controls (p<0.05)
Summary of litter parameters
Dose level |
0 mg/kg bw/d |
3 mg/kg bw/d |
10 mg/kg bw/d |
30 mg/kg bw/d |
Number of females inseminated |
16 |
16 |
16 |
16 |
Pregnancy rate (%) |
87.5 |
93.8 |
100.0 |
100.0 |
No. of pregnant females |
13 |
13 |
15 |
8 |
Number of litters with live foetuses |
13 |
13 |
13 |
7 |
Mean number of corpora lutea |
11.7 |
11.4 |
11.0 |
10.1 |
Mean number of implantations |
8.3 |
7.6 |
8.3 |
5.7 |
Mean implantation efficiency (%) |
72.5 |
67.9 |
76.8 |
61.5 |
Mean number of resorptions |
1.7 |
1.2 |
1.3 |
1.1 |
Mean incidence of resorptions (%) |
18.4 |
15.0 |
22.4 |
21.1 |
Mean incidence of foetal viability (%) |
81.6 |
84.0 |
77.6 |
78.9 |
Mean number of live foetuses per litter |
6.6 |
6.4 |
6.9 |
4.6 |
Mean number of dead foetuses per litter |
0.0 |
0.1 |
0.0 |
0.0 |
Mean percent of males per litter |
60.0 |
40.0 |
48.4 |
66.9 |
Mean fetal weight (g) |
|
|
|
|
Male |
44.6 |
43.6 |
41.1 |
48.0 |
Female |
42.9 |
42.6 |
40.5 |
45.0 |
Summary of foetal findings
Dose level |
0 mg/kg bw/d |
3 mg/kg bw/d |
10 mg/kg bw/d |
30 mg/kg bw/d |
Number of foetuses (fetal incidence %) |
||||
Total number of foetuses examined |
86 |
83 |
104 |
32 |
External malformations |
1 (1.2) |
0 (0.0) |
3 (2.9) |
0 (0.0) |
External variations |
0 (0.0) |
0 (0.0) |
1 (1.0) |
0 (0.0) |
Visceral malformations |
0 (0.0) |
2 (2.4) |
0 (0.0) |
0 (0.0) |
Visceral variations |
4 (4.7) |
1 (1.2) |
5 (4.8) |
1 (3.1) |
Skeletal malformations |
2 (2.3) |
6 (7.2) |
4 (3.8) |
0 (0.0) |
Skeletal variations |
67 (78) |
64 (77) |
79 (76) |
25 (78) |
Number of litter (litter incidence %) |
||||
Total number of litters examined |
13 |
13 |
13 |
7 |
External malformations |
1 (7.7) |
0 (0.0) |
2 (15) |
0 (0.0) |
External variations |
0 (0.0) |
0 (0.0) |
1 (7.7) |
0 (0.0) |
Visceral malformations |
0 (0.0) |
2 (15) |
0 (0.0) |
0 (0.0) |
Visceral variations |
3 (23) |
1 (7.7) |
4 (31) |
1 (14) |
Skeletal malformations |
1 (7.7) |
2 (15) |
3 (23) |
0 (0.0) |
Skeletal variations |
13 (100) |
13 (100) |
13 (100) |
7 (100) |
Summary of clinical signs
Dose level |
0 mg/kg bw/d |
3 mg/kg bw/d |
8 mg/kg bw/d |
25 mg/kg bw/d |
GD6-16 (treatment period) |
||||
Number of animals observed |
24 |
24 |
24 |
24 |
Thin |
1 |
3 |
1 |
7 |
Tremors |
0 |
0 |
0 |
9 |
Rhinorrhea |
0 |
1 |
0 |
6 |
Rough haircoat |
0 |
0 |
0 |
7 |
Urine stains |
0 |
1 |
0 |
10 |
GD17-20 (post-treatment period) |
||||
Number of animals observed |
24 |
24 |
24 |
24 |
Thin |
0 |
1 |
0 |
3 |
Tremors |
0 |
0 |
0 |
5 |
Rhinorrhea |
0 |
0 |
0 |
5 |
Rough haircoat |
0 |
0 |
0 |
5 |
Urine stains |
0 |
0 |
0 |
2 |
Summary of bodyweight effects
Dose level |
0 mg/kg bw/d |
3 mg/kg bw/d |
8 mg/kg bw/d |
25 mg/kg bw/d |
Mean body weight (g) |
||||
GD 0 |
238 |
241 |
237 |
237 |
GD 6 |
268 |
270 |
264 |
262 |
GD 7 |
266 |
266 |
263 |
261 |
GD 8 |
267 |
269 |
265 |
261 |
GD 9 |
270 |
275 |
269 |
262 |
GD 10 |
277 |
280 |
274 |
265 |
GD 11 |
283 |
286 |
280 |
269* |
GD 12 |
287 |
290 |
284 |
273* |
GD 13 |
289 |
295 |
286 |
276* |
GD 14 |
294 |
301 |
293 |
278* |
GD 15 |
301 |
309 |
300 |
281* |
GD 16 |
310 |
319 |
311 |
286* |
GD 17 |
323 |
332 |
325 |
301* |
GD 18 |
337 |
347 |
339 |
315* |
GD 19 |
349 |
362 |
356 |
331* |
GD 20 |
362 |
378 |
370 |
347 |
Body weight change (g) |
||||
GD 0-6 |
30 |
29 |
27 |
26 |
GD 6-7 |
-2 |
-3 |
-2 |
-1 |
GD 6-8 |
-1 |
-1 |
1 |
-1 |
GD 6-9 |
2 |
5 |
4 |
-0.2 |
GD 6-10 |
9 |
11 |
9 |
3* |
GD 6-11 |
15 |
17 |
15 |
7* |
GD 6-12 |
19 |
21 |
19 |
10* |
GD 6-13 |
21 |
26 |
22 |
13* |
GD 6-14 |
26 |
31 |
28 |
15* |
GD 6-15 |
33 |
39 |
36 |
19* |
GD 6-16 |
42 |
49* |
47 |
24* |
GD 6-17 |
55 |
63 |
61 |
38* |
GD 6-18 |
69 |
77 |
75 |
52* |
GD 6-19 |
81 |
92* |
91 |
68 |
GD 6-20 |
94 |
108* |
106* |
84 |
GD 16-20 |
52 |
59* |
59* |
60* |
GD 0-20 |
124 |
137* |
133 |
110 |
*significantly different to controls (p<0.05)
Uterus weights
Dose level |
0 mg/kg bw/d |
3 mg/kg bw/d |
8 mg/kg bw/d |
25 mg/kg bw/d |
Mean terminal body weight (g) |
361.7 |
377.5 |
370.2 |
346.7 |
Mean gravid uterine weight (g) |
71.8 |
81.4* |
82.2* |
73.4 |
Mean corrected terminal body weight (g) |
289.9 |
296.1 |
288.1 |
273.3* |
*significantly different to controls (p<0.05)
Litter parameters
Dose level |
0 mg/kg bw/d |
3 mg/kg bw/d |
8 mg/kg bw/d |
25 mg/kg bw/d |
Number of females mated |
24 |
24 |
24 |
24 |
Number of litters with live fetuses |
24 |
22 |
20 |
20 |
Mean number of corpora lutea |
16.0 |
16.8 |
18.0 |
16.0 |
Mean number of implantations |
14.0 |
15.3 |
15.8 |
14.1 |
Mean implantation efficiency (%) |
88 |
92 |
89 |
87 |
Mean number of resorptions |
0.9 |
0.5 |
1.0 |
0.8 |
Mean incidence of resorptions (%) |
6 |
3 |
6 |
7 |
Mean incidence of fetal viability (%) |
94 |
97 |
94 |
93 |
Mean number of live fetuses per litter |
13.1 |
14.7 |
14.8 |
13.3 |
Mean number of dead fetuses per litter |
0 |
0 |
0 |
0 |
Mean percent of males per litter |
49 |
51 |
48 |
50 |
Mean fetal weight (g) |
|
|
|
|
Male |
3.5 |
3.5 |
3.6 |
3.5 |
Female |
3.3 |
3.4 |
3.3 |
3.3 |
Foetal parameters
Dose level |
0 mg/kg bw/d |
3 mg/kg bw/d |
8 mg/kg bw/d |
25 mg/kg bw/d |
Number of fetuses (fetal incidence %) |
||||
Total number of fetuses examined |
314 |
324 |
295 |
265 |
External malformations |
0 (0.0) |
0 (0.0) |
1 (0.3) |
1 (0.4) |
External variations |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
Total number of fetuses examined |
158 |
164 |
146 |
135 |
Visceral malformations |
1 (0.6) |
0 (0.0) |
1 (0.7) |
0 (0.0) |
Visceral variations |
35 (22) |
38 (23) |
33 (23) |
22 (16) |
Total number of fetuses examined |
156 |
160 |
149 |
130 |
Skeletal malformations |
0 (0.0) |
0 (0.0) |
0 (0.0) |
1 (0.8) |
Skeletal variations |
71 (46) |
95 (59) |
78 (52) |
72 (55) |
Number of litter (litter incidence %) |
||||
Total number of litters examined |
24 |
22 |
20 |
20 |
External malformations |
0 (0.0) |
0 (0.0) |
1 (5.0) |
1 (5.0) |
External variations |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
Total number of litters examined |
24 |
22 |
20 |
20 |
Visceral malformations |
1 (4.2) |
0 (0.0) |
1 (5.0) |
0 (0.0) |
Visceral variations |
18 (75) |
16 (73) |
15 (75) |
9 (45) |
Total number of litters examined |
24 |
22 |
20 |
20 |
Skeletal malformations |
0 (0.0) |
0 (0.0) |
0 (0.0) |
1 (5.0) |
Skeletal variations |
21 (88) |
20 (91) |
20 (100) |
19 (95) |
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 10 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Guideline-compliant studies of prenatal developmental toxicity in the rat and rabbit are available for fenitrothion.
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Toxicity to reproduction: other studies
Additional information
In a developmental toxicity study, groups of 24 time-mated female Sprague-Dawley Crl:CD®(SD)BR rats were gavaged with fenitrothion (dissolved in corn oil) at dose levels of 0, 3, 8 and 25 mg/kg bw/d from Gestation Days 6-15 of gestation, using a dose volume of 5 mL/kg bw. Dams were sacrificed on GD20 and the uterine contents examined. All foetuses were assessed for extranal findings. Approximately one half of the foetuses in each litter were preserved in Bouin's and assessed for visceral findings using Wilson's technique; the remaining foetuses were assessed for skeletal findings following staining with Alizarin Red S. All females survived until the scheduled sacrifice. Signs of toxicity noted at 25 mg/kg bw/d during the treatment and post-treatment intervals included tremors, rough hair, thin appearance, rhinorrhoea and urine staining. There was a significant decrease in the mean maternal body weights each day on GD11-19 at 25 mg/kg bw/d. The mean terminal (GD20) bodyweight in the 25 mg/kg bw/d group was slightly, but not significantly, less than the control value. However, the mean corrected terminal body weight was significantly less in the 25 mg/kg bw/d group when compared to controls. The mean maternal body weight gain values were significantly lower in the 25 mg/kg bw/d group during the treatment period compared to the control group. The mean body weight gain values in the 3 and 8 mg/kg bw/d groups were significantly above the control values for the post-treatment period. Food consumption values were comparable between the control and treated groups. Gross necropsy did not reveal any effects of treatment. Mean gravid uterine weights were significantly higher for the 3 and 8 mg/kg bw/d groups when compared to the control value. Mean gravid uterine weight at 25 mg/kg bw/d was similar to the controls. There were no differences between groups in the pregnancy rates, mean implantation efficiency, foetal viability, foetal sex ratio, or mean foetal body weights. Neither the frequency nor the distribution of foetal malformations indicated a teratogenic response in any group in this study. There was no evidence of teratogenicity or developmental toxicity in this study at dose levels sufficient to result in mild maternal toxicity. A maternal NOAEL of 8 mg/kg bw/d can be determined for this study, based on clinical signs and bodyweight effects at the highest dose level of 25 mg/kg bw/d. A developmental NOAEL of 25 mg/kg bw/d can be determined in the absence of any effects at the highest dose level.
In a developmental toxicity study, groups of 16 inseminated female HRA(NZW)SPF rabbits each received fenitrothion dissolved in corn oil, at dose levels of 0, 3, 10 and 30 mg/kg bw/d by oral gavage, daily from Days 7 to 19 of gestation at the dosage volume of 1.0 mL/kg bw. Clinical observations, body weights and food consumption were recorded for all females. On day 29 of gestation, all surviving pregnant females were sacrificed and a cesarean section performed. All live fetuses were evaluated for external findings, visceral findings (Staples' technique) and for skeletal findings following staining with Alizarin Red S.A total of six pregnant females receiving 30 mg/kg/ bwd were found dead during the treatment period and three pregnant females aborted or delivered prematurely (GD 22-29). One female receiving 10 mg/kg bw/d was found dead on GD18, and one control female was found dead on GD 8. Both females were anorexic prior to death. The two deaths in the 3 mg/kg bw/d group were the result of dosing errors (verified at necropsy). Anorexia was frequently noted in all groups during the treatment and posttreatment periods. Treatment-related clinical signs in rabbits receiving 30 mg/kg bw/d included reduction in motor activity, salivation, dyspnoea, and tremors. These signs were not seen in any animals of the control, 3 and 10 mg/kg bw/d groups at the pre-treatment and Mean body weight changes were significantly decreased for pregnant females receiving 30 mg/kg bw/d on GD7-13. These animals also displayed values slightly lower than the control for GD0-29 but this difference was not statistically significant.post-treatment intervals, with only one incidence of reduced motor activity (10 mg/kg bw/d group) noted during treatment, in the decedent rabbit. Significantly decreased food consumption values were observed for pregnant females receiving 3 mg/kg bw/d on GD9-13 and were significantly increased for animals receiving 30 mg/kg bw/d on GD26-29 in addition to a significant negative trend on GD7-8. All other mean food consumption values were statistically similar for all groups. Gross necropsy did not reveal any effects of treatment. The mean number of implantations was lower in the high dose group, resulting in a lower litter size. Other parameters were unaffected by treatment. There was no dose-related increase in the incidence of any particular malformation or in the incidence of any type (i.e. external, visceral, or skeletal) of malformation. Although the litter incidence of skeletal malformations was slightly higher than controls in the 3 and 10 mg/kg bw/d groups, no malformations were noted in the seven litters of the 30 mg/kg bw/d group available for evaluation. Overt evidence of maternal toxicity was seen in animals receiving 30 mg/kg/ bwd but was not accompanied by adverse effects on foetal growth or development. Maternal and developmental NOAELs of 10 mg/kg bw/d can be determined for this study, based on maternal toxicity (mortality, clinical signs, bodyweight effects) and reduced litter size at the highest dose level.
Justification for classification or non-classification
Fenitrothion has a harmonised classification but is not classified for reproductive toxicity. In the absence of relevant findings in the available studies, no change to this classification is proposed. There was no evidence of any effects of treatment on fertility or reproductive capacity in the two-generation study. No developmental toxicity was obserfved in the rat study at maternally toxic dose levels. Effects in the rabbit study were limited to reduced numbers of implantations and litter size at the highest dose level. Effects were associated with maternal toxicity inlcuding mortality, and are therefore considered to be secondary and non-specific and are not relevant for the purposes of classification.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
